Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair

Lu, Yanxin; Kwintkiewicz, Jakub; Liu, Yang; Tech, Katherine; Frady, Lauren N.; Su, Yu Ting; Bautista, Wendy; Moon, Seog In; Macdonald, Jeffrey M.; Ewend, Matthew G.; Gilbert, Mark R.; Yang, Chunzhang; Wu, Jing

doi:10.1158/0008-5472.can-16-2773

Cited by 174 publications

(138 citation statements)

References 38 publications

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…We did not identify a similar association in a panel of human chondrosarcoma cell lines. Likewise, the synthetic lethal interaction between temozolomide and IDH mutations described in gliomas was not observed in our study [35,36]. Our research group published that the reported synthetic lethal interaction between IDH mutations and Bcl-2, NAMPT, and glutaminase inhibition was absent in chondrosarcoma [11,[37][38][39].…”

Section: Discussioncontrasting

confidence: 46%

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Venneker

Kruisselbrink

Bruijn

et al. 2019

Cancers

View full text Add to dashboard Cite

Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose–response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma.

show abstract

Section: Discussioncontrasting

confidence: 46%

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Venneker

Kruisselbrink

Bruijn

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…A recent study combined an ATM kinase inhibitor with TMZ to treat brain cancer and found that this combination sensitized highly resistant glioma cells to chemotherapies (49). The combination of a NAD þ /PARP inhibitor with TMZ is a recently developed chemotherapy regimen, which has shown promising effects against gliomas with pathogenic IDH1 mutations (36,37,50,51). Furthermore, PARP inhibitor was found sensitizing chemoresistant malignant melanoma for TMZ administration (52).…”

Section: Combination Of a Parp Inhibitor And Tmz Suppressed Sdhb-mutamentioning

confidence: 99%

Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma

Pang

Caisová

et al. 2018

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ()-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with knockdown PCPG allograft. In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with mutations..

show abstract

“…Cells were treated with TG02 (50 nmol/L), TMZ (100 mmol/L), and both drugs for 48 hours. The extracellular acidification rate (ECAR) was recorded and calculated for basal glycolysis and glycolytic capacity (19). Reagents, including 10 mmol/L Glucose, 2 mmol/L oligomycin, and 50 mmol/L 2-deoxy-glucose (2-DG), were added as per the supplier's technical specifications.…”

Section: Extracellular Acidification Rate Measurementmentioning

confidence: 99%

Novel Targeting of Transcription and Metabolism in Glioblastoma

Chen

Wang

et al. 2018

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become an effective therapeutic for GBM patients.Experimental Design: To investigate TG02, an agent with known penetration of the blood-brain barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We used human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis, and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays.Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of antiapoptotic proteins and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-induced decrease of CDK9 phosphorylation was confirmed in the brain tumor tissue.Conclusions: TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial.

show abstract

Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair

Cited by 174 publications

References 38 publications

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma

Novel Targeting of Transcription and Metabolism in Glioblastoma

Contact Info

Product

Resources

About